This invention related to a group of 1,2-disubstituted 1,4-dihydro-4-oxoquinoline compounds and the use of said compounds as an antiviral agent.
The enteroviruses, rhinoviruses and hepatovirus are three groups within the family Picornaviridae which cause a wide range of human viral disease. The enterovirus group comprises 67 distinct serotypes, including 3 strains of poliovirus, 23 group A and 6 group B coxsackieviruses, 31 echoviruses, and 4 the newer numbered enteroviruses. Enteroviruses cause a broader range disease syndrome including xe2x80x9csummer fluxe2x80x9d, upper respiratory illness, acute hemorrhagic conjunctivitis, hand, foot and mouth disease, myocarditis, aseptic meningitis, and poliomyelitis. Hepatitis A virus (HAV) was provisionally classified as enterovirus type 72. However, later studies have demonstrated several characteristics that distinguish HAV from other picornaviruses. It is concluded that HAV is a unique member of the family Picornaviridae, resulting in its classification into a new genus, Hepatovirus. HAV is a common cause of both sporadic and epidemic acute hepatitis in humans, produces substantial morbidity. Among the agents of viral hepatitis, HAV is most prevalent, but it is clinically less important than the hepatitis B and C virus. The clinical manifestations of HAV infection in humans can vary greatly, ranging from asymptomatic infection, commonly seen in young children, to fulminant hepatitis, which in some cases can result in death.
Human rhinovirus (HRV), which include over 100 different serotypes are the most important etiological agents of the common cold. Infection of the upper respiratory tract by members of the HRV group represents perhaps the most common viral affliction of humans, accounting for some 40 to 50% of common colds. Although HRV-induced upper respiratory illnesses often mild and self-limiting, severe disease can occur in subjects predisposed to respiratory problems, such as asthmatics. From an economic standpoint, rhinovirus infections of humans represent a significant health problem in terms of numbers of physicians"" office visits, costs associated with symptomatic treatments and days lost from work and school.
Thus, infections with more than 200 different serotypes of picornavirus cause significant morbidity and mortality. The vast serotypic diversity of these viruses precludes development of vaccines for the control of human infection by these virus groups except for poliovirus and hepatitis A virus. Currently, there is no specific antiviral therapy to treat or prevent picornavirus infections.
Rotaviruses are the single most important etiologic agents of severe diarrheal illness of infant and young children world-wide. Although diarrheal diseases are one of the most common illness of infant and young children throughout the world, they assume a special significance in less developed countries, where they constitute a major cauase of mortality among the young. Rotavirus infection produces a spectrum of responses that vary from subclinical infection to mild diarrhea to a severe and occasionally fatal dehydrating illness. At present, neither a vaccine nor specific antiviral medication has been discovered for human rotavirus infections.
We have found that a group of 1,4-dihydro-4-oxoquinoline derivatives have a potent antiviral activity against picornaviruses and rotaviruses.
The present invention provides a 1,2-disubstituted 1,4-dihydro-4-oxoquinoline compound of Formula I: 
wherein each R1 is a member independently selected from the group consisting of alkyl, cycloalkyl, phenyl, alkoxy, cycloalkyloxy, phenoxy, methylenedioxy, trifluoromethyl, halogen, OH, NO2, NH2, mono- or dialkylamino, pyrrolidino, piperidino, piperazino, 4-hydroxypiperazino, 4-methylpiperazino, 4-acetylpiperazino, morpholino, pyridyl, pyridyloxy, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiomorpholino, dialkylaminoalkylamino, N-alkylaminoalkyl-N-alkylamino, N-hydroxyalkyl-N-alkylamino, dialkylaminoalkoxy, acetoxy, hydroxycarbonyloxy, alkoxycarbonyloxy, hydroxycarbonylmethoxy and alkoxycarbonylmethoxy, and n is 1,2 or 3;
wherein R2 is a member selected from the group consisting of alkyl, pyridyl, pyrazinyl, furyl, N-alkylpyrrolyl, thiazolyl, thienyl which may be optionally substituted with alkyl or halogen, and phenyl which may be optionally substituted with up to two substituents independently selected from the group consisting of halogen, OH, alkyl, alkoxy, trifluoromethyl and acetoxy;
wherein R3 is a member selected from the group consisting of hydrogen, alkyl, phenyl, alkoxy, alkoxycarbonyl, alkylsulfonyl, CN and acetyl; or
if R2 is a phenyl group optionally substituted with halo, alkyl or alkoxy groups, R3 may represent a bridging group between the 3rd position of the quinoline ring and said phenyl group at a position next to the ring carbon atom at which said phenyl group is directly connected to the quinoline ring, said bridging group being selected from the group consisting of methylene, carbonyl, hydroxyiminomethylidene, alkoxyiminomethylidene, alkanoylaminomethylidene, aminomethylidene, hydroxymethylidene, 1-hydroxy-1,1-alkylidene, xcex1-hydroxybenzylidene, 1-alkoxy-1,1-alkylidene, xcex1-alkoxybenzylidene, 1,2-ethylidene and 1,3-propylidene; or
if R2 is 2-thienyl, 4- or 5-alkyl-2-thienyl or N-alkylpyrrol-3-yl, R3 may represent methylene bridge between the 3rd position of the quinoline ring and said thienyl group at the 3rd position or said pyrrolyl group at the 2nd position, and
wherein R4 is a member selected from the group consisting of alkyl, alkenyl, benzyl and phenyl optionally substituted with halo, alkyl or alkoxy.
In a preferred embodiment, the compound of the present invention has Formula I-a: 
wherein R2xe2x80x2 is phenyl or substituted phenyl having up to two substituents independly selected from the group consisting of halo, OH, alkyl, alkoxy, trifluoromethyl and acetoxy;
R3xe2x80x2 is hydrogen, alkyl, phenyl, alkoxy, alkoxycarbonyl, alkyl-sulfonyl, CN or acetyl; and
R1, R4 and n are as defined above.
In another embodiment, the compound of the present invention has Formula I-b: 
wherein R2xe2x80x3 is alkyl, pyridyl, pyrazinyl, furyl, N-alkylpyrrolyl, thienyl, substituted thienyl having up to two halo- or alkyl substituents, or thiazolyl; and
R1, R3xe2x80x2, R4 and n are as defined above.
In other embodiments, if R2 is pheny or substituted phenyl in the formula I, R3 may be a bridge forming a fused ring system including the quinoline and benzene rings.
When the bridge is formed of a single carbon atom, the compound of the present invention is a derivative of 5,6-dihydro-11H-indeno[1,2-b]quinoline of Formula I-c: 
wherein R5 is a member independly selected from the group consisting of hydrogen, halo, alkyl and alkoxy;
R6 and R7 together with the carbon atom to which they are attached represent a bridge selected from the group consisting of methylene, carbonyl, hydroxyiminomethylidene, alkoxyiminomethylidene, alkanoylaminomethylidene, aminomethylidene, hydroxymethylidene, 1-hydroxy-1,1-alkylidene, xcex1-hydroxybenzylidene, 1-alkoxy-1,1-alkylidene and xcex1-alkoxybenzylidene;
m is 1 or 2; and
R1, R4 and n are as defined above.
When the bridge is 1,2-ethylidene, the compound of the present invention is a derivative of 6,12-dihydrobenzo[c]-acridine of Formula I-d; 
wherein R1, R4, R5, n and m are as defined above.
When the bridge is 1,3-propylidene, the compound of the present invention is a derivative of 5,6,7,13-tetrahydro-8H-benzo[6,7]cyclohepta[1,2-b]quinoline of Formula I-e; 
wherein R1, R4, R5, n and m are as defined above.
In further embodiments, if R2 is thienyl, 4- or 5-alkyl-2-thienyl or N-alkyl-pyrrol-3-yl, R3 may be a methylene bridge forming a fused ring system including the quinoline ring and the thiophene or pyrrole ring. Thus, the compounds of the present invention include a derivative of thieno[3xe2x80x2,2xe2x80x2:4,5]-cyclopenta[1,2-b]quinoline-5-one of Formula I-f: 
wherein R8 is hydrogen or alkyl; and
R3, R4 and n are as defined above.
Also included in the compounds of the present invention is a derivative of pyrrolo[3xe2x80x2,2xe2x80x2:4,5]cyclopenta[1,2-b]quinoline-5-one of Formula I-g: 
wherein R9 is alkyl, and R1, R4 and n are as define.
The compounds of the present invention also include a pharmaceutically acceptable acid addition salt or quaternary ammonium salt thereof.
The invention also relates to a pharmaceutical composition comprising a compound of Formula I above and a pharmaceutically acceptable carrier. The pharmaceutical composition of the invention is useful in the prophylaxis and the treatment of viral infections of Picornavirus and human rotavirus.
Throughout the specification and claims, several terms are difined as follows.
Alkyl including the alkyl moiety of alkoxy refers to a straight chain or branched alkyl of up to 8, preferably 6 carbon atoms.
Alkenyl refers to an alkenyl of 2-6, preferably 3-4 carbon atoms.
Cycloalkyl refers to a cycloalkyl of 5-7 carbon atoms, preferably cyclohexyl.
Halogen refers to fluorine, chlorine or bromine.
The compounds of Formula I may be synthesized by use of known chemical reactions and procedures starting from appropriately substituted aniline II.
Generally, the synthesis of the compounds of Formula I follows either Method A or Method B. In Method A, substituted anilines II are reacted with 2-benzoylalkanoic acid ethyl ester III in the presence of polyphosphoric acid to give 2-phenyl-4-oxoquinoline derivatives (IV) followed by the reaction with R4I in the presence of sodium hydride. Method A is applicable to the synthesis of the compounds of Formula I-a. 
In Method B, the compounds of formula I are prepared from substituted anilines II via N-substituted isatoic anhydrides VIII.
The intermediate VIII, in turn, may be synthesized by two methods as shown in Scheme II below. Substituted anilines II are reacted with chloral hydrate and hydroxylamine to yield nitrosoacetanilide V. Cyclization of V into substituted isatins VI followed by introduction of R4 at position 1 yields N-substituted isatins VII. N-substituted isatoic anhydrides VIII are obtained by treating VII with m-chloroperbenzoic acid(m-CPBA). Alternatively, N-substituted isatoic anhydride VIII may be prepared by reacting isatins VI with m-CPBA to produce N-unsubstituted isatoic anhydrides IX followed by introduction of R4 at position 1. N-substituted isatins VII may also be prepared by reacting N-substituted anilines XII with oxalyl chloride followed by aluminum chloride. N-substituted anilines XII, in turn, may be prepared by acetylating substituted anilines II, reacting the resulting acetanilides X with an alkylating agent to introduce R4 followed by deacetylation of the N-substituted acetanilides XI. 
N-Substituted isatoic anhydrides VIII are used in Method B for the synthesis of the compounds of Formula I by the reaction with an appropriate ketone in the presence of n-butyl lithium and tetramethylethylenediamine (TMEDA) or in the presence of sodium hydride.
In Method B1 for the preparation of the compounds of Formula I-a, the ketone compound may be represented by the formula: R2xe2x80x2C(O)CH2R3xe2x80x2, wherein R2xe2x80x2 is phenyl or substituted phenyl having one or two substituents independently selected from the group consisting of halo, OH, alkyl, alkoxy, trifluoromethyl and acetoxy; and R3xe2x80x2 is hydrogen, alkyl, phenyl, alkoxy, alkoxycarbonyl, alkylsulfonyl, CN or acetyl. The reaction involved in Method B1 is shown in Scheme III. 
Similarly, Method B2 for the preparation of the compounds I-b, a ketone of the formula: R2xe2x80x3C(O)CH2R3xe2x80x2, wherein R2xe2x80x3 is alkyl, pyridyl, pyrazinyl, furyl, N-alkylpyrrolyl, thienyl, substituted thienyl having up to two halo- or alkyl substituent or thiazolyl; and R3xe2x80x2 is as defined above is used. The reaction involved in Method B2 is shown in Scheme IV. 
The compounds of Formula I-c wherein both R6 and R7 are hydrogen as well as the compounds of Formula I-d and Formula I-e are prepared by Method B3 shown in Scheme V. 
Specifically, the oxo compound XIII are 1-indanones for the compounds of Formula I-c(x=1, R6, R7=H), 1-tetralones for the compounds Formula I-d (x=2) and 1-oxobenzosuberones (x=3), respectively.
The compounds of Formula I-c wherein R6 and R7 together represent oxo may be prepared by reacting the isatoic anhydride VIII with a 1,3-indandione XIV to obtain 5,10-dihydro-11H-indeno[1,2-b]quinolin-10,11-dione compounds XV as shown in Scheme VI. 
The 11-oxo compounds XV may be further manipulated using known methodoloy to obtain the compounds of Formula I-c wherein R6 and R7 are other than oxo. Reaction of 11-oxo compounds XV with hydroxylamine gives a corresponding oxime. Reaction of oxime with an alkylating agent in the presence of sodium hydride gives a 11-alkoxyimino compound. The oxime further gives a 11-alkanoylamino compound by acylation with an acylating agent such as acetyl anhydride in a reducing atomosphere. Saponification of 11-alkanoylamino compound leads to 11-amino compound.
The 11-oxo compounds XV may be converted into a 11-hydroxy compound by the reaction with sodium borohydride. Reaction of 11-oxo compounds XV with alkyl- or phenyl magnesium halide leads to a 11-hydroxy-11-alkyl or phenyl devivative. The hydroxy group at position 11 may further be alkylated in the presence of sodium hydride to give a 11-alkoxy-11-alkyl or phenyl derivative. The hydroxy group at position 11 may be removed by the reaction with sodium iodide and trimethylsilyl chloride to give 11-alkyl or phenyl derivative.
Finally, the compounds of Formula I-f and Formula I-g may be prepared by Method B4 as shown in Scheme VII. The compounds of Formula I-f are prepared by the reaction of isatoic anhydride VIII with 4,5-dihydro-6H-cyclopenta[b]-thiophen-6-one XVI in the presence of n-BuLi and TMEDA. Reaction of isatoic anhydride VIII with 1-methyl-5,6-dihydro-4H-cyclopenta[b]pyrrol-4-one XVII in the presence of n-BuLi and TMEDA gives the compounds of Formula I-g. 